https://onlinelibrary.wiley.com/doi/pdf/10.1002/jor.1100090504

Mesenchymal stem cells

Targeted Disruption of Cbfa1 Results in a Complete Lack of Bone Formation owing to Maturational Arrest of Osteoblasts

In the last 10 years, a large family of secreted signaling molecules has been discovered that appear to mediate many key events in normal growth and development. The family is known as the TGF-p superfamily (Massague 1990), a name taken from the first member of the family to be isolated (transforming growth factor-^l). This name is somewhat misleading, because TGF-p 1 has a large number of effects in different systems (Spom and Roberts 1992). It actually inhibits the proliferation of many different cell lines, and its original "transforming" activity may be due to secondary effects on matrix pro­ duction and synthesis of other growth factors (Moses et al. 1990). The two dozen other members of the TGF-p superfamily have a remarkable range of activities. In Diosophila, a TGF-p-related gene is required for dorsoventral axis formation in early embryos, communication between tissue layers in gut development, and correct proximal distal patterning of adult appendages. In Xenopus, a TGF-p-related gene is expressed specifically at one end of fertilized eggs and may function in early signaling events that lay out the basic body plan. In mammals, TGF-p-related molecules have been found that control sexual development, pituitary hormone production, and the creation of bones and cartilage. The recognition of TGF-p superfamily members in many different organ­ isms and contexts provides one of the major unifying themes in recent molecular studies of animal growth and development. The rough outlines of the TGF-p family were first rec­ ognized in the 1980s. Since that time, a number of ex­ cellent reviews have appeared that summarize the prop­ erties of different family members (Ying 1989; Massague 1990; Lyons et al. 1991; Spom and Roberts 1992). Here, I will focus on four areas that have seen major progress in the last 3 years: structural characterization of the signal­ ing molecule, isolation of new family members, cloning of receptor molecules, and new genetic tests of the func­ tions of these factors in different organisms.

/pdf/the-tgf-beta-superfamily-new-members-new-receptors-and-new-4idj1n7bhx.pdf

The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms.

/pdf/bone-morphogenetic-proteins-multifunctional-regulators-of-2uv2zp3r0o.pdf

Bone morphogenetic proteins: multifunctional regulators of vertebrate development.

Osteochondral progenitor cells were used to repair large, full-thickness defects of the articular cartilage that had been created in the knees of rabbits. Adherent cells from bone marrow, or cells from the periosteum that had been liberated from connective tissue by collagenase digestion, were grown in culture, dispersed in a type-I collagen gel, and transplanted into a large (three-by-six-millimeter), full-thickness (three-millimeter) defect in the weight-bearing surface of the medial femoral condyle. The contralateral knee served as a control: either the defect in that knee was left empty or a cell-free collagen gel was implanted. The periosteal and the bone-marrow-derived cells showed similar patterns of differentiation into articular cartilage and subchondral bone. Specimens of reparative tissue were analyzed with use of a semiquantitative histological grading system and by mechanical testing with employment of a porous indenter to measure the compliance of the tissue at intervals until twenty-four weeks after the operation. There was no apparent difference between the results obtained with the cells from the bone marrow and those from the periosteum. As early as two weeks after transplantation, the autologous osteochondral progenitor cells had uniformly differentiated into chondrocytes throughout the defects. This repair cartilage was subsequently replaced with bone in a proximal-to-distal direction, until, at twenty-four weeks after transplantation, the subchondral bone was completely repaired, without loss of overlying articular cartilage. The mechanical testing data were a useful index of the quality of the long-term repair. Twenty-four weeks after transplantation, the reparative tissue of both the bone-marrow and the periosteal cells was stiffer and less compliant than the tissue derived from the empty defects but less stiff and more compliant than normal cartilage. Clinical Relevance: The current modalities for the repair of defects of the articular cartilage have many disadvantages. The transplantation of progenitor cells that will form cartilage and bone offers a possible alternative to these methods. As demonstrated in this report, autologous, bone-marrow-derived, osteochondral progenitor cells can be isolated and grown in vitro without the loss of their capacity to differentiate into cartilage or bone. Sufficient autologous cells can be generated to initiate the repair of articular cartilage and the reformation of subchondral bone. The repair tissues appear to undergo the same developmental transitions that originally led to the formation of articular tissue in the embryo.(ABSTRACT TRUNCATED AT 400 WORDS)

Mesenchymal Cell-Based Repair of Large Full Thickness Defects of Articular Cartilage

Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene family, while the third, BMP-1, appears to be a novel regulatory molecule.

https://science.sciencemag.org/content/sci/242/4885/1528.full.pdf

Lisa M. Mitsock

Papers

Novel regulators of bone formation: molecular clones and activities.

Novel Regulators of Bone Formation: Molecular Clones and Activities